DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group III (claims 81-99) in the reply filed on 02/09/2026 is acknowledged. The traversal is on the ground(s) that Groups I-III are linked by the special technical feature of an antisense oligonucleotide comprising a sequence of nucleobases that is complementary to a target region in an intron-retaining SCN2A mRNA or pre-mRNA, wherein the target region is in a retained intron and wherein the retained intron is selected from the group consisting of intron 1, 2, 3, 4, 5, 11, 17, and 24. This is not found persuasive. As previously set forth, Stoke Therapeutics (of record) discloses that the TANGO system removes retained introns from non-productive SCN2A mRNA, thereby increasing productive mRNA, which is in turn translated into increased protein expression (page 8, paragraph 1 and associated figures; page 71, paragraph 2; table-page 11). While Stoke Therapeutics (of record) does not disclose targeting introns 1, 2, 3, 4, 5, 11, 17, and 24 specifically, as previously set forth Aznarez (of record) discloses therapeutic antisense agents which can target non-productive mRNA transcripts to modulate the expression level of function proteins (i.e. SCN2A) in patients by targeting improperly retained intron 1, 2, 3, 4, 5, 11, 17, or 24, as instantly claimed (abstract; paragraphs [0012], [00119], and [00139]). While Aznarez does disclose a number of possible intron targets, Applicant’s own disclosure teaches that SCN2A has a known, finite number of introns (see Figure 1; paragraph [0031] of the instant specification) testable by those of ordinary skill in the art. Thus, one of ordinary skill in the art would have been motivated by the disclosure of Stoke Therapeutics to target SCN2A for removal of retained introns, while Aznarez motivates the use of antisense agents to target said retained introns for removal, wherein said intron may be improperly retained intron 1, 2, 3, 4, 5, 11, 17, or 24.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1 and 52-80 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 02/09/2026.
Upon further consideration, the restriction requirement between Group I and Group II as set forth in the Office action mailed on 11/07/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Accordingly, claims 81-99 are pending and under consideration.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The earliest effective filing date to which the instant application is entitled is 07/22/2020.
Information Disclosure Statement
Receipt of information disclosure statements on 05/24/2023, 01/23/2025, 02/11/2025, and 02/09/2026 is acknowledged. The signed and initialed PTO-1449‘s have been mailed with this action.
Drawings
The drawings are objected to because:
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”
In the current case, the view numbers for Figures 1-7 are preceded by the word "Figure" instead of the abbreviation "FIG.". It would be remedial to precede the view numbers for Figures 1-7 with the abbreviation “FIG.”.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See paragraph [00130]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 82, 83, 87, 88, and 90 are objected to because of the following informalities:
Claim 82 recites “the antisense oligonucleotide binds to…nucleotides with an RNA secondary structure” (bolded emphasis added), which is phrased awkwardly. It would be remedial to amend the instant claim language to recite binding to nucleotides that have RNA secondary structure in a more easily readable/interpretable manner.
Claim 83 recites the term “a heterogenous nuclear ribonucleoproteins (hnRNP)” (bolded emphasis added). The singular article “a” is not consistent with the recited plural “ribonucleoproteins.” In order to comport with standard grammatical and/or linguistic conventions, it would be remedial to ensure that all recited articles are consistent with the recited terms.
Claims 87, 88, and 90 all recite sequence identifiers. Proper recitation of a sequence identifier includes the sequence identifier prefix (SEQ ID NO(s)), a colon, a space, and the identifier number(s). Claims 87, 88, and 90 do not consistently follow this format. For example, claim 87 recites “SEQ ID NOs:115-205,” which lacks the space separating the sequence identifier prefix and the identifier number(s) itself/themselves. It would be remedial to ensure all recited sequence identifiers are formatted correctly.
Appropriate correction is required.
Claim Interpretation
The Examiner notes that independent claim 81, from which all other examined claims directly or indirectly depend, recites “the retained intron is selected from the group consisting of intron 1, 2, 3, 4, 5, 11, 17 and 24.” Therefore, any antisense oligonucleotide targeting any of the recited introns is considered to read on the instantly claimed antisense oligonucleotide. While claims 85, 86, 89, and 90 recite specific targeting of intron 2 of SCN2A, as set forth above, any antisense oligonucleotide targeting any of the recited introns is considered to read on the instantly claimed antisense oligonucleotide. It is thus not considered that the antisense oligonucleotide is required to target only intron 2 of SCN2A, as any antisense oligonucleotide targeting any of introns 1, 2, 3, 4, 5, 11, 17 and 24 reads on the instantly claimed oligonucleotide.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 87 and 90-93 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 87 and 90-93 are drawn to a set of antisense oligonucleotides targeting retained intron 1, 2, 3, 4, 5, 11, 17, or 24 of SCN2A mRNA or pre-mRNA. The antisense oligonucleotide may comprise a sequence having at least 70% identity to any one of SEQ ID NOs: 115-205 (instant claim 87) or a sequence comprising at least 8 contiguous nucleotides from any one of SEQ ID NOs: 143-205 (instant claim 90). Further, the antisense oligonucleotide may consist of 8 to 50 nucleotides (instant claim 91). Finally, the antisense oligonucleotide may be at least 70% complementary to the target region (instant claim 92) or may be 100% complementary to the target region over a length of at least 8 contiguous nucleobases (instant claim 93). The rejected claims thus comprise a set of antisense oligonucleotides that encompass a wide range of possible sequences and variants thereof, all versions of which must target retained intron 1, 2, 3, 4, 5, 11, 17, or 24 of SCN2A mRNA or pre-mRNA.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes antisense oligonucleotides targeting retained intron 2 in SCN2A, said antisense oligonucleotides corresponding to SEQ ID NOs: 115-205 (Tables 2 and 3), all of which are 18 nucleotides in length. No description is provided of any variants of these antisense oligonucleotides, either with respect to sequence identity or with respect to antisense oligonucleotide length.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of SEQ ID NOs: 115-205. The results are not necessarily predictive of variants of these antisense oligonucleotides, such as those comprising at least 70% sequence identity thereto or those comprising 8 nucleotides. Thus, it is impossible for one to extrapolate from the examples described herein those antisense oligonucleotides that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of antisense oligonucleotides comprising at least 70% sequence identity to the claimed antisense oligonucleotides, nor does it describe a set of antisense oligonucleotides comprising 8 nucleotides, as instantly claimed. Chan et al., 2006 (hereinafter Chan) reviews principles of designing antisense oligonucleotides. While antisense oligonucleotides are short, they are typically about 20 base pairs in length, and their efficacy depends strongly on the sequence of the antisense oligonucleotide, as hybridization of the antisense oligonucleotide to the target mRNA is what facilitates specific inhibition of gene expression (see Chan sections “SUMMARY” and “INTRODUCTION”; see also Figure 1). A length of 8 nucleotides (as instantly claimed) is substantially shorter than 20 nucleotides. Furthermore, it is known to those of ordinary skill in the art that sequence length is correlated with target specificity, as increasing the number of targetable nucleotides increases the number of distinguishable sequences (reviewed in Dervan, 1986: see Table 1). A sequence of 8 nucleotides can only target an estimated 32,896 unique sites; whereas, increasing the sequence length to 10 exponentially increases the number of targetable unique sites (to 524,800) (reviewed in Dervan, 1986: see Table 1). Therefore, an antisense oligonucleotide with the substantial sequence composition and length variation claimed herein would not reasonably be expected to function in the same manner as SEQ ID NOs: 115-205, all of which are 18 nucleotides in length and comprise sequences capable of targeting SCN2A via hybridization to SCN2A.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 87 and 90-93.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 85 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 85 recites the limitation "the ISS" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 85 depends from claim 81, which does not recite an ISS. For purposes of examination and in the interest of compact prosecution, claim 85 has been interpreted to depend from claim 82, which does recite an ISS. It would be remedial to amend the instant claim set such that there is sufficient antecedent basis for every recited claim term.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 81, 86, 89-97, and 99 are rejected under 35 U.S.C. 103 as being unpatentable over Stoke Therapeutics Fiscal Year 2019 SEC Disclosure (hereinafter Stoke Therapeutics; as cited in the IDS filed 05/24/2023; of record), WO 2019/084050 A1 (hereinafter Aznarez; of record), and Tavassoli et al., 2014 (hereinafter Tavassoli), as evidenced by Richards and Hawley, 2011 (hereinafter Richards) and Chan, 2006 (hereinafter Chan).
With regard to claim 81, which recites “an antisense oligonucleotide comprising a sequence of nucleobases that is complementary to a target region in an intron-retaining SCN2A mRNA or pre-mRNA, wherein the target region is in a retained intron and wherein the retained intron is selected from the group consisting of intron 1, 2, 3, 4, 5, 11, 17 and 24,” as previously set forth, Stoke Therapeutics discloses the TANGO system, which targets non-productive mRNA containing retained introns with antisense oligonucleotides to redirect the splicing machinery to remove said retained introns, thereby increasing productive mRNA, which is in turn translated into increased protein expression (page 8, paragraph 1 and associated figures; page 71, paragraph 2). SCN2A is specifically recited as a gene believed to be amenable to manipulation with the TANGO technique (table-page 11). However, Stoke Therapeutics does not disclose targeting of a retained intron selected from the group consisting of intron 1, 2, 3, 4, 5, 11, 17, and 24, as instantly claimed.
This deficiency is cured by Aznarez, which discloses therapeutic antisense agents which can target non-productive mRNA transcripts to modulate the expression level of functional proteins in patients and/or to inhibit aberrant protein expression (abstract; paragraph [0012]). Aznarez further discloses targeting an SCN2A nonsense-mediated mRNA decay-inducing exon (NIE) (found within an intron and improperly retained during alternative or aberrant splicing events) within intron 1, 2, 3, 4, 5, 11, 17, or 24, as instantly claimed (paragraphs [00119] and [00139]).
Furthermore, Tavassoli discloses that a splice site mutation involving intron 4 of SCN2A is implicated in autism spectrum disorder (abstract; Figure 1). This mutation is in the donor site of intron 4 of the longest isoform on SCN2A (page 3, column 1, paragraph 5-page 3, column 2, paragraph 1). As is known to those of ordinary skill in the art, mutations to splice donor sites in introns result in improper intron retention (reviewed in Richards: see Figure 5.15). Thus, it is considered that Tavassoli discloses a mutation in intron 4 of SCN2A that results in improper intron retention of intron 4, thereby affecting SCN2A function.
Accordingly, it is considered that Stoke Therapeutics, Aznarez, Tavassoli, and Richards collectively disclose each and every additional limitation of instant claim 81.
With regard to claim 86, which recites “the retained intron [of the antisense oligonucleotide of claim 81] is intron 2 and the target region spans positions -4 --- +14…relative to the 5’ splice site of intron 2,” as set forth above (see section Claim Interpretation), claim 86 does not require targeting of retained intron 2 by the antisense oligonucleotide of instant claim 81. Instead, claim 86 further limits the targeting of retained intron 2, which is not required by the instant claim language of claim 81. Accordingly, it is considered that the therapeutic antisense oligonucleotide collectively disclosed and/or motivated by Stoke Therapeutics, Aznarez, Tavassoli, and Richards also reads on the antisense oligonucleotide of instant claim 86.
With regard to claim 89, which recites “the retained intron [of the antisense oligonucleotide of claim 81] is intron 2 and the target region spans positions -19 --- -1…relative to the 3’ splice site of intron 2,” as set forth above (see section Claim Interpretation), claim 86 does not require targeting of retained intron 2 by the antisense oligonucleotide of instant claim 81. Instead, claim 89 further limits the targeting of retained intron 2, which is not required by the instant claim language of claim 81. Accordingly, it is considered that the therapeutic antisense oligonucleotide collectively disclosed and/or motivated by Stoke Therapeutics, Aznarez, Tavassoli, and Richards also reads on the antisense oligonucleotide of instant claim 89.
With regard to claim 90, which recites “the antisense oligonucleotide [of claim 89] comprises the sequence set forth in any one of SEQ ID NOs:143-205 [sic], or a sequence comprising at least 8…contiguous nucleotides from a sequence set forth in any one of SEQ ID NOs: 143-205,” as set forth above, it is considered that the therapeutic antisense oligonucleotide collectively disclosed and/or motivated by Stoke Therapeutics, Aznarez, Tavassoli, and Richards also reads on the antisense oligonucleotide of instant claim 89, from which instant claim 90 depends. Given that instant claim 90 further limits the antisense oligonucleotide targeting retained intron 2, which is not required by instant claim 81 (see section Claim Interpretation), it is considered that the therapeutic antisense oligonucleotide collectively disclosed and/or motivated by Stoke Therapeutics, Aznarez, Tavassoli, and Richards also reads on the antisense oligonucleotide of instant claim 90.
With regard to claim 91, which recites “the antisense oligonucleotide [of claim 81] consists of from 8 to 50…nucleobases,” as set forth above, Aznarez discloses therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]). These antisense oligonucleotides are further disclosed to be 8-50 nucleobases in length (paragraph [00190], as instantly claimed. Thus, it is considered that Aznarez discloses each and every additional limitation of instant claim 91.
With regard to claim 92, which recites “the antisense oligonucleotide [of claim 81] is at least 70%...complementary to the target region,” as set forth above, Aznarez discloses therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]). These antisense oligonucleotides are further disclosed to have exact (i.e. 100%) sequence complementarity to the target sequence (paragraph [00169]). Given that 100% is greater than 70%, it is considered that Aznarez discloses each and every additional limitation of instant claim 92.
With regard to claim 93, which recites “the antisense oligonucleotide [of claim 81] comprises at least 8…contiguous nucleobases that are 100% complementary to the target region,” as set forth above, Aznarez discloses therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]). These antisense oligonucleotides are further disclosed to be 8-50 nucleobases in length (paragraph [00190], as instantly claimed. Furthermore, these antisense oligonucleotides are further disclosed to have exact (i.e. 100%) sequence complementarity to the target sequence (paragraph [00169]). Thus, it is considered that Aznarez discloses each and every additional limitation of instant claim 93.
With regard to claim 94, which recites “the antisense oligonucleotide [of claim 81] comprises at least one modification,” as set forth above, Aznarez discloses therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]). These antisense oligonucleotides are further disclosed to comprise modified sugar moieties such as 2’-O-methyl (paragraph [00179]) and/or backbone modifications, such as a phosphorothioate backbone (paragraph [00181]) to alter the properties of the antisense oligonucleotide, for example to enhance binding affinity to a target sequence, reduce binding to any non-target sequence, reduce degradation by cellular nucleases, improve uptake, alter the pharmacokinetics, and/or to modulate the half-life of the antisense oligonucleotide (paragraph [00181]). Thus, it is considered that Aznarez discloses each and every additional limitation of instant claim 94.
With regard to claim 95, which recites “the modification [of the antisense oligonucleotide of claim 94] is a nucleobase modification, a modification of the oligonucleotide backbone or a modification of a ribose sugar,” as set forth above, Aznarez discloses therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]). These antisense oligonucleotides are further disclosed to comprise modified sugar moieties such as 2’-O-methyl (paragraph [00179]) and/or backbone modifications, such as a phosphorothioate backbone (paragraph [00181]) to alter the properties of the antisense oligonucleotide, for example to enhance binding affinity to a target sequence, reduce binding to any non-target sequence, reduce degradation by cellular nucleases, improve uptake, alter the pharmacokinetics, and/or to modulate the half-life of the antisense oligonucleotide (paragraph [00181]). Thus, it is considered that Aznarez discloses each and every additional limitation of instant claim 95.
With regard to claim 96, which recites “the antisense oligonucleotide [of claim 81] comprises a modified sugar selected from the group consisting of a 2’-O-methyl (2OMe)…,” as set forth above, Aznarez discloses therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]). These antisense oligonucleotides are further disclosed to comprise modified sugar moieties such as 2’-O-methyl (paragraph [00179]. Thus, it is considered that Aznarez discloses each and every additional limitation of instant claim 96.
With regard to claim 97, which recites “the antisense oligonucleotide [of claim 81] comprises a backbone that comprises phosphorothioates, as set forth above, Aznarez discloses therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]). These antisense oligonucleotides are further disclosed to comprise backbone modifications, such as a phosphorothioate backbone (paragraph [00181]). Thus, it is considered that Aznarez discloses each and every additional limitation of instant claim 97.
With regard to claim 98, which recites “the antisense oligonucleotide [of claim 81] activates RNase H,” while Aznarez discloses that the therapeutic antisense oligonucleotides taught therein may be modified to reduce degradation by cellular nucleases such as RNase H (paragraph [00181]), they do not explicitly disclose that the antisense oligonucleotides taught therein activate RNase H. However, it is known that antisense oligonucleotides effect target knockdown by a number of mechanisms, including activation of RNase H upon formation of an antisense oligonucleotide-mRNA heteroduplex, thereby knocking down the target gene (Chan: Figure 1). Accordingly, it is considered that antisense oligonucleotides (such as those disclosed in Aznarez) are known to function by activating RNase H, as in instant claim 98. Thus, it is considered that Aznarez and Chan collectively disclose each and every additional limitation of instant claim 98.
With regard to claim 99, which recites “a composition comprising the antisense oligonucleotide of claim 81,” as set forth above, Aznarez discloses therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]). Aznarez further discloses that the antisense oligomers taught therein are provided within a therapeutic composition (paragraph [00169]), as instantly claimed. Thus, it is considered that Aznarez discloses each and every additional limitation of instant claim 99.
Given that Stoke Therapeutics discloses therapeutic targeting of SCN2A with antisense oligonucleotides for removal of retained introns, that Aznarez discloses targeting introns 1, 2, 3, 4, 5, 11, 17, or 24 of SCN2A, and that Tavassoli discloses that retained intron 4 of SCN2A (see also Richards) is associated with autism spectrum disorder, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to target retained intron 4 of SCN2A (as disclosed in Tavassoli) with antisense oligonucleotides (as disclosed in Stoke Therapeutics, Azanrez, and Chan) to predictably remove retained intron 4, thereby treating autism spectrum disorder. One would have been motivated to make such a modification in order to receive the expected benefit of removing retained intron 4, thereby treating autism spectrum disorder.
Claims 82-85 are rejected under 35 U.S.C. 103 as being unpatentable over Stoke Therapeutics Fiscal Year 2019 SEC Disclosure (hereinafter Stoke Therapeutics; as cited in the IDS filed 05/24/2023; of record), WO 2019/084050 A1 (hereinafter Aznarez; of record), and Tavassoli et al., 2014 (hereinafter Tavassoli), as evidenced by Richards and Hawley, 2011 (hereinafter Richards) and Chan, 2006 (hereinafter Chan) as applied to claim 81 above, and further in view of WO 2015/193651 A1 (hereinafter Vorechovsky), as evidenced by Havens and Hastings, 2016 (hereinafter Havens).
The combined disclosures of Stoke Therapeutics, Aznarez, Tavassoli, Richards, and Chan are described above and applied as before. However, these disclosures do not teach the antisense oligonucleotide targeting limitations of instant claims 82-85.
With regard to claim 82, which recites “the antisense oligonucleotide [of claim 81] binds to, or adjacent to, an intron splicing silencer (ISS), binds to nucleotides within a G-quadruplex, or binds to nucleotides with an RNA secondary structure,” as set forth above, Stoke Therapeutic discloses that the TANGO system taught therein utilizes antisense oligonucleotides to redirect splicing machinery to remove the retained intron (page 10, paragraph 1), while Aznarez and Tavassoli respectively disclose therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]), specifically retained intron 4 (abstract; Figure 1). However, the cited art does not teach that the antisense oligonucleotides disclosed therein bind to an intron splicing silencer, as instantly claimed. This deficiency is cured by Vorechovsky.
Vorechovsky discloses methods, compositions, and polynucleic acid polymers for inducing removal of a retained intron (abstract). These polynucleic acid polymers are further disclosed to be antisense polynucleic acid polymers, wherein the antisense sequence may hybridize to an intronic splicing silencer to modulate splicing (paragraphs [0069] and [0070]). Thus, it is considered that Vorechovsky discloses each and every additional limitation of instant claim 82.
With regard to claims 83 and 84, which respectively recite “the ISS [of the antisense oligonucleotide of claim 82] is recognized by a heterogeneous nuclear ribonucleoproteins [sic] (hnRNP),” specifically “hnRNAP1 or hnRNP1,” as set forth above, Vorechovsky discloses methods, compositions, and antisense polynucleic acid polymers for inducing removal of a retained intron, wherein said antisense polynucleic acid polymers hybridize to an intronic splicing silencer to modulate splicing (abstract; paragraphs [0069] and [0070]). Vorechovsky further discloses that the targeted intronic splicing silencers are processed by hnRNPA1 (paragraph [0070]). This is further supported by the teachings of Havens, which discloses that ISS sequences are recognized by hnRNPA1 (page 6557, column 2, paragraph 2). Thus, it is considered that Vorechovsky (as evidenced by Havens) discloses each and every additional limitation of instant claims 83 and 84.
With regard to claim 85, which recites “the antisense oligonucleotide of claim [82-see section Claim Rejections - 35 USC § 112(b)], wherein the retained intron is intron 2 and the ISS is at positions +8 --- +12…relative to the 3’ splice site of intron 2,” as set forth above (see section Claim Interpretation), claim 85 does not require targeting of retained intron 2 by the antisense oligonucleotide of instant claims 81 or 82. Instead, claim 85 further limits the targeting of retained intron 2, which is not required by the instant claim language of claims 81 or 82. Accordingly, it is considered that the therapeutic antisense oligonucleotide collectively disclosed and/or motivated by Stoke Therapeutics, Aznarez, Tavassoli, Richards, and Vorechovsky also reads on the antisense oligonucleotide of instant claim 85.
Given that Stoke Therapeutics, Aznarez, Tavassoli, Richards, and Chan collectively disclose the antisense oligonucleotide of instant claim 81, and that Vorechovsky discloses antisense polynucleic acids for the removal of retained introns, wherein said antisense polynucleic acids hybridize to an intronic splicing silencer that canonically binds hnRNPA1 (as taught in Havens), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the antisense oligonucleotides of instant claim 81 to target ISS sequences that are recognized by hnRNPA1 to predictably facilitate proper retained intron removal. One would have been motivated to make such a modification in order to receive the expected benefit of properly splicing SCN2A transcripts, thereby generating functional SCN2A.
Claims 87 and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Stoke Therapeutics Fiscal Year 2019 SEC Disclosure (hereinafter Stoke Therapeutics; as cited in the IDS filed 05/24/2023; of record), WO 2019/084050 A1 (hereinafter Aznarez; of record), and Tavassoli et al., 2014 (hereinafter Tavassoli), as evidenced by Richards and Hawley, 2011 (hereinafter Richards) and Chan, 2006 (hereinafter Chan) as applied to claim 81 above, and further in view of US 7,485,449 B2 (hereinafter Rouleau).
The combined disclosures of Stoke Therapeutics, Aznarez, Tavassoli, Richards, and Chan are described above and applied as before. However, these disclosures do not teach the antisense oligonucleotide sequences of instant claims 87 and 88.
With regard to claims 87 and 88, which respectively recite “the antisense oligonucleotide [of claim 81] comprises a sequence…having at least 8…contiguous nucleotides from a sequence set forth in any one of SEQ ID NOs: 115-205,” specifically “at least 8…contiguous nucleotides from a sequence set forth in SEQ ID NO:126 [sic], SEQ ID NO:138 [sic] or SEQ ID NO:155 [sic],” as set forth above, Stoke Therapeutic discloses that the TANGO system taught therein utilizes antisense oligonucleotides to redirect splicing machinery to remove the retained intron (page 10, paragraph 1), while Aznarez and Tavassoli respectively disclose therapeutic antisense agents targeting SCN2A (abstract; paragraphs [0012], [00119], and [00139]), specifically retained intron 4 (abstract; Figure 1). However, the cited art does not disclose the instantly claimed antisense oligonucleotide sequences. This deficiency is cured by Rouleau.
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The Examiner notes that the instant specification defines an “antisense oligonucleotide” as “a single-stranded oligonucleotide having a sequence that permits hybridization to a corresponding region or segment of a target nucleic acid.” Therefore, any single-stranded oligonucleotide that hybridizes to a target nucleic acid must read on the instantly claimed “antisense oligonucleotide.” In view of this definition, Rouleau discloses PCR primers used for genomic PCR-SSCP of SCN2A at Figure 4. PCR-SSCP is well-known in the art and is used to detect mutations as small as single-base substitutions (column 17, line 54-column 18, line 3). As disclosed at Example 4 of Rouleau, primers specific to SCN2A were used to amplify genomic DNA from IGE and normal patients, followed by SSCP analysis to identify mutations in SCN2A (column 26, lines 41-61). These PCR primers depicted at Figure 4 include SEQ ID NO: 200. As shown in the alignment below, SEQ ID NO: 200 of Rouleau shares 15 contiguous nucleotides with instant SEQ ID NO: 126, which corresponds to 83.3% shared sequence identity.
Thus, Rouleau discloses each and every additional limitation of instant claims 87 and 88.
Given that Stoke Therapeutics, Aznarez, Tavassoli, Richards, and Chan collectively disclose the antisense oligonucleotide of instant claim 81, and that Rouleau discloses PCR primers specific to SCN2A, including SEQ ID NO: 200, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to specifically target SCN2A with antisense oligonucleotides (as disclosed in Stoke Therapeutics, Aznarez, Tavassoli, Richards, and Chan) comprising a sequence specific to SCN2A (as disclosed in Rouleau) to predictably target retained introns in SCN2A for removal, thereby producing functional SCN2A. One would have been motivated to make such a modification in order to receive the expected benefit of targeting retained introns in SCN2A for removal, thereby producing functional SCN2A.
Conclusion
No claims are allowed.
Claims 82, 83, 87, 88, and 90 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-Th 8-5, F 8-12.
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/SARAH E ALLEN/Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637
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